Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The PTEN tumor suppressor gene encodes a dual-specificity protein phosphatase that may play a key role in modulating integrin-mediated signals. Inactivation of the PTEN gene has been detected in a small percentage of clinically localized prostate cancers but is common in metastatic disease. It has been shown in glioblastoma cell lines that loss of chromosome 10q, where the PTEN gene is located, is associated with increased angiogenic activity in the conditioned medium attributable to downregulation of thrombospondin-1, a negative regulator of angiogenesis. Therefore, we wished to determine whether inactivation of PTEN might be associated with increased angiogenesis in prostate cancers, because increased angiogenesis in localized cancers is associated with development of metastatic disease. Angiogenesis was assessed by counting microvessels in areas of maximal neovascularization after immunostaining with anti-factor VIII-related antigen antibodies in eight cases with proven homozygous deletion of the PTEN gene and 24 control cases. There was a statistically significant correlation between PTEN inactivation and increased microvessel counts. The microvessel density was higher at all Gleason scores in the cases with PTEN inactivation compared with control cases with the same score. To determine whether the increased angiogenesis in cases with PTEN inactivation was caused by downregulation of expression of the angiogenesis inhibitor thrombospondin-1, we analyzed a subset of the cases by immunostaining with anti-thrombospondin-1 antibody. Approximately 25% of cases showed decreased staining of prostate cancer cells, but there was no correlation with PTEN inactivation. Thus, PTEN inactivation is associated with increased angiogenesis, but the increased angiogenesis is not attributable to downregulation of thrombospondin-1 expression.
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PMID:Inactivation of the PTEN tumor suppressor gene is associated with increased angiogenesis in clinically localized prostate carcinoma. 1020 63

A tumor suppressor gene at 10q 23.3, designated PTEN, encoding a dual specificity phosphatase with lipid and protein phosphatase activity, has been shown to play an important role in the pathogenesis of a variety of human cancers. Germline mutations in PTEN cause Cowden syndrome (CS), which is characterized by multiple hamartomas and a high risk of breast and thyroid cancers. Frequent loss of heterozygosity at 10q is found in both early and advanced-stage sporadic melanomas; however, mutations or deletions in PTEN are detected mainly in melanoma cell lines. In this study, we examined PTEN expression in 34 unselected sporadic melanomas (4 primary melanomas, 30 metastases) using immunohistochemistry and correlated this with the results of structural studies of this gene. Immunostaining of 34 melanoma samples revealed no PTEN expression in 5 (15%) and low PTEN expression in 17 (50%), whereas the rest of the tumors (35%) had high levels of expression. Hemizygous deletion was found in 32% of the tumors but neither intragenic PTEN mutation nor biallelic deletion was found in any of the samples. Of the 5 melanomas showing no PTEN expression, 4 had no mutation or deletion of PTEN. Of the 13 tumors having weak PTEN immunoreactivity and informative loss of heterozygosity results, 6 had evidence of hemizygous allelic loss of PTEN while the remaining 7 had intact PTEN. These results strongly support PTEN as a major tumor suppressor on 10q involved in melanoma tumorigenesis and suggest an epigenetic mechanism of biallelic functional inactivation not previously observed in other cancers where PTEN might be involved.
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PMID:Epigenetic PTEN silencing in malignant melanomas without PTEN mutation. 1102 16

Motility and adhesiveness are regulated by a multitude of factors, including cytoskeletal polymerization and phosphorylation of cytoskeletal and associated proteins. The metastatic Lewis lung carcinoma variant, LLC-LN7, was highly motile in vitro and had lower levels of the serine/threonine protein phosphatase PP-2A than did the nonmetastatic variant, LLC-C8. Reducing PP-2A activity of the nonmetastatic cells pharmacologically or with catalytic (Calpha) subunit antisense increased their in vitro motility. Nonmetastatic LLC-C8 cells had a greater proportion of polymerized tubulin which co-purified with PP-2A as compared to the metastatic LLC-LN7 cells. The PP-2A that was associated with the microtubules of these cells showed similar ratios of the Aalpha structural subunit to the Calpha/beta catalytic subunits. In contrast, the proportion of the regulatory subunit B56alpha was lower in the nonmetastatic LLC-C8 cells as compared to the metastatic LLC-LN7 cells. These studies show the role of PP-2A in restricting the motility of nonmetastatic tumor cells and suggest that the loss of this regulatory control in metastatic LLC-LN7 cells may be due to both a reduction in microtubule-associated PP-2A and a difference in the composition of the subunits of PP-2A that is associated with the microtubules.
Clin Exp Metastasis 2000
PMID:Differences in association of the serine/threonine protein phosphatase PP-2A with microtubules of metastatic and nonmetastatic tumor cells. 1146 73

PTEN is a dual-specificity phosphatase with both protein phosphatase and lipid phosphatase activity. PTEN is the first phosphatase identified as a tumor suppressor. Not since the discovery of p53 has a tumor suppressor generated such interest. Initial studies performed on cancer cell lines suggested that PTEN may be responsible for almost all types of cancer, both solid tumors and hematological malignancies. Biallelic deletion of PTEN has been associated with advanced stage tumors or metastatic disease. PTEN has been shown to play a pivotal role in apoptosis, cell cycle arrest, and possibly cell migration. Emerging data suggest that this may be an oversimplification of PTEN's role, and that PTEN may be haploinsufficient for tumor progression and may play important roles in other cellular functions such as angiogenesis and MAP kinase signaling.
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PMID:PTEN regulatory functions in tumor suppression and cell biology. 1544 14

Patients with premalignant oral lesions have varying levels of risk of developing oral squamous cell carcinoma (OSCC), whose aggressiveness requires increased motility. Not known is if and how premalignant oral lesion cells acquire the increased motility characteristic of OSCC. This was addressed by immunohistochemical analysis of banked premalignant lesion tissues and by functional analyses using cultures established from premalignant oral lesions and OSCC. These studies showed premalignant oral lesion cells and OSCC to be more motile than normal keratinocytes. Concomitantly, levels of ceramide were reduced. The activity of the protein phosphatase PP-2A, which restricts motility and which can be activated by ceramide, was also diminished. This was due to IL-10 released from premalignant lesion cells. Treatment with a membrane-permeable ceramide restored PP-2A activity and blocked migration. These studies show an autocrine motility-stimulatory pathway that is mediated in premalignant lesion cells by IL-10 through its reduction of ceramide levels and inhibition of PP-2A activity.
Clin Exp Metastasis 2007
PMID:Autocrine motility-stimulatory pathways of oral premalignant lesion cells. 1737 39

Although the aberrant actions of protein kinases have long been known to contribute to tumor promotion and carcinogenesis, roles for protein phosphatases in the development of human cancer have only emerged in the last decade. In this review, we discuss the data obtained from studies examining the biological and pathological roles of a serine/threonine protein phosphatase, PP5, which suggest that PP5 is a potentially important regulator of both hormone- and stress-induced signaling networks that enable a cell to respond appropriately to genomic stress.
Cancer Metastasis Rev 2008 Jun
PMID:The role of serine/threonine protein phosphatase type 5 (PP5) in the regulation of stress-induced signaling networks and cancer. 1825 12

Protein tyrosine phosphatase, PTPL1, (also known as PTPN13, FAP-1, PTP-BAS, PTP1E) is a non-receptor type PTP and, at 270 kDa, is the largest phosphatase within this group. In addition to the well-conserved PTP domain, PTPL1 contains at least 7 putative macromolecular interaction domains. This structural complexity indicates that PTPL1 may modulate diverse cellular functions, perhaps exerting both positive and negative effects. In accordance with this idea, while certain studies suggest that PTPL1 can act as a tumor-promoting gene other experimental studies have suggested that PTPL1 may function as a tumor suppressor. The role of PTPL1 in the cancer cell is therefore likely to be both complex and context dependent with possible roles including the modulation of growth, stress-response, and cytoskeletal remodeling pathways. Understanding the nature of molecular complexes containing PTPL1, its interaction partners, substrates, regulation and subcellular localization are key to unraveling the complex personality of this protein phosphatase.
Cancer Metastasis Rev 2008 Jun
PMID:PTPL1: a large phosphatase with a split personality. 1826 46

Tensin is a family of multidomain scaffold proteins that bind the cytoplasmic tail of beta-integrins and localize to adhesions that anchor stress fibers in cells. Tensin expression is suppressed in cancer, especially metastatic cancer. The N-terminal domain of tensin1 associates with protein phosphatase-1alpha (PP1alpha) and mediates PP1alpha localization to adhesions. Here, we show F302A mutation in a KVXF motif of tensin1 abrogates binding to PP1alpha. The SH2 domain in tensin family member c-ten requires R474 to bind a RhoGAP called DLC-1 (deleted in liver cancer). We mutated the corresponding residue in tensin1, R1488A, and showed this reduces association with DLC-1. Unexpectedly, tensin1 F302A also had reduced association with DLC-1. Expression of tensin1 F302A or R1488A showed similar dominant phenotypes, with reduced cell polarization, lowered MLC20 phosphorylation and reduced levels of RhoA(GTP) compared with cells expressing tensin1 WT. However, migration and invasion of metastatic MDA MB 231 breast cancer cells were differentially affected by tensin1 mutated at F302A or R1488A. Cancer cells stably expressing F302A tensin1 showed increased migration and invasion compared with cells stably expressing either R1488A tensin1 or WT tensin1. This suggests that PP1alpha bound to tensin1 has additional effects in reducing migration and invasion that are not mediated through DLC-1. Our results show the importance of PP1alpha binding to tensin1 for the regulation of cell polarization, migration, and invasion.
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PMID:Tensin1 requires protein phosphatase-1alpha in addition to RhoGAP DLC-1 to control cell polarization, migration, and invasion. 1982 1

The tumor suppressor PTEN is a phosphatase using FAK and Shc as direct substrates, and Akt as a key effector via PIP3. PTEN regulates cell migration and may influence metastases. We quantified PTEN in 135 clear cell renal cell carcinomas (ccRCC) by Western blot analysis and found statistically significant lower PTEN expression in patients who died, usually caused by metastases, within 5 years after surgery, compared to those surviving this time period. In athymic mice, PTEN transfected 786-O cells were injected into the tail vein and metastatic load of the lungs was quantified. We observed a strongly reduced metastatic load after PTEN transfection. For analyses of the PTEN activities, transfections with mutated PTEN genes were performed, leading to loss of lipid phosphatase activity and/or protein phosphatase activity, and of the C-terminal tail. Cell migration was analyzed in a Boyden chamber and phosphorylation of PTEN downstream targets Akt, FAK and Shc by Western blotting. 786-O cells transfected with the functional PTEN gene showed profoundly diminished migration. Transfection with a mutated PTEN isoform leading to loss of protein phosphatase activity, but not of lipid phosphatase activity, abolished this effect. Shc but not FAK seems to mediate this effect. These results show a critical role of PTEN in metastasis of RCC, depending on protein phosphatase activity via Shc. This new insight opens an alley of additional approaches complementing current cancer therapy and metastasis prediction in RCC.
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PMID:Migration of renal tumor cells depends on dephosphorylation of Shc by PTEN. 2120 72

Dual-specificity protein phosphatase 4 (DUSP4), a negative regulator of extracellular-regulated kinase activity, is a potential mediator of resistance to chemotherapy and a tumor suppressor. The aim of this study is to clarify the association between DUSP4 gene expression and clinical outcome in patients with colorectal cancer. Patients who underwent surgery for colorectal cancer were enrolled in this study (n = 212). We investigated DUSP4 gene expression by real-time reverse transcription polymerase chain reaction in colorectal cancer tissue and paired normal mucosa. Immunohistochemical analyses of DUSP4 and ERK1/2 were also conducted. Additionally, we examined the relationship between gene expression and KRAS mutation in 74 of the 212 patients. DUSP4 expression in tumor tissues was significantly higher than that in matched normal mucosa (P < 0.0001). Decreased DUSP4 expression was significantly associated with advanced T classification, lymphatic invasion, vascular invasion, advanced stage, and liver and lung metastases. Logistic regression analysis revealed that decreased DUSP4 expression was an independent risk factor for synchronous distant metastases (P = 0.006). Increased DUSP4 expression was significantly associated with better prognosis (P = 0.0162). Immunohistochemical examination showed DUSP4 expression in the nucleus and cytoplasm of cancer cells, and no correlation was observed between DUSP4 and ERK1/2 expression. There was no significant correlation between DUSP4 expression and KRAS mutation. In conclusion, DUSP4 expression in colorectal cancer was negatively correlated with factors reflecting tumor progression, including distant metastases. Our data suggest that DUSP4 may act as a tumor suppressor in colorectal cancer.
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PMID:Decreased expression of DUSP4 is associated with liver and lung metastases in colorectal cancer. 2374 51


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